17 alpha-(lower-alkyl)-19-nor-5(10)-androstene-3, 17beta-diols



3,976,826 17 a-(LQWERALKY Lyw-NGR QME-ANDRG- STENE-Zsfiifl-EEULS Raymond0. Clinton, North Greenhush Township, Robert G. Christiansen, Schodak(Ienter, N.Y., assignors to Sterling Drug line, New York, N.Y., acorporation of Delaware No Drawing. Filed Aug. 2d, 3957, er. No. 679,1192 Claims. (Cl. ass-oars This invention relates to new chemical compoundsof the steroid series and in particular concerns a series of3-X-l7ot-(lower-alkyl)-19-norandrosten-lTfi-Ols having a double bond inthe 5(10)-position, wherein X is a hydroxy radical, and to a process forthe preparation of said compounds.

The compounds of the invention possess the following structural formula:

can

Weak acid lower-alkyl-Q Line Estrone lower-alkyl ether (I1) isallcylated at the l7-posi tion with an alkylrnagnesium halide in aconventional Grignard reaction to give al'ia-(lower-alkyD-3,l7fl-estradiol 3-loWer-alkyl other (111). The latteris then reduced with lithium metal in liquid ammonia and alcohol to givea dihydrocompound (IV). Structure 1V is an enol loweralkyl ether whichcan be hydrolyzed under mild conditions, e.g., in the presence of a weakacid to give a compound having the Formula I where X represents an oxoradial, that is, a t-(loWer-alkyl)-l9-nor-5(l0)-androsten-l7 3-ol-3-one.Metal hydride reduction of the latter gives a corresponding compoundwherein X represents a hydroxy radical, that is, al7et-(lower-alliyl)-19-nor- 5(l0)-androstene-3,l7fi-diol. The compoundsof For mula lll where R represents the ethyl group can a1ternatively beprepared by reacting estrone lower-alkyl ether with a metal derivativeof acetylene in a Net reaction, followed by catalytic hydrogenation ofthe resulting 17aethynyl derivative (ill; R is CEH).

The lower-alkyl radicals attached to oxygen in the 3-position ofstructures ll, Ill and IV preferably have from one to about four carbonatoms, and thus can be methyl, ethyl, propyl, isopropyl, butyl,isobutyl, and the like.

The hydrolysis of the enol ether (IV) to the unsaturated ltetone (I; Xis Q) is carried out by treating the enol ether with a Weak acid in aloWer-alkanol which acts as a solvent for the steroid. The use of strongacids should "be avoided since these will cause rearrangement of thedouble bond from the 5(l0)-position to the 4,5-position in conjugationwith the 0X0 group. Any Weak acid will serve the desired purpose, apreferred class being organic carboxylic acids which are appreciablysoluble in loweralkanols or aqueous lower-alkanols. An especiallypreferred Weak acid is oxalic acid. The hydrolysis will take place atroom temperature or can be carried out by means of gentle heating ifdesired.

The metal hydride reduction of the unsaturated ketones (I; X is O) tothe corresponding unsaturated alcohols takes place in an inert solventat room temperature or With gentle heating. Appropriate metal hydridcsare lithium aluminum hydride, sodium borohydride, sodium hydride, andthe like, the first named being a preferred reducing agent.

The structures of the compounds of the invention were proved by the modeof synthesis and are consistent with elementary analysis and uitravioletand infrared spectra data. For example, the compounds of Formula I,where X is 0:, absorb in the ultraviolet at about 280 um, and not atabout 240 mu, characteristic of conjugated, 11,5-

3 unsaturated ketones. Hence the double bond remaining after partialhydrogenation of the aromatic system in ring A must lie in the positionunconjugated with the oxo group, i.e., in the (10)-position.

The following examples Will further illustrate the invention without thelatter being limited thereby.

EXAMPLE 1 (a) 17cz-methyl-2,5(10)-estradiene-3,17fi-di0l 3-mathyl ether[IV; R is CH L-A S-liter, three-necked, round bottomed flask was fittedwith a Dry Ice condenser, a glass stirrer and an addition funnel. Thesystem was flamedried and 1300 cc. of liquid ammonia was added to theflask. There was then added a solution of 16.00 g. (0.0512 mole) of 17r-methyl-3,17,8-estradio-l 3-methyl ether [111; R is CH in 1000 cc. ofether, followed by 8.00 g. (1.15 moles) of lithium wire in one inchportions. Over a period of one-half hour there was then added 175 cc. ofabsolute ethanol. The majority of the ammonia was allowed to evaporate,the solvent was removed on a steam bath, and ice water was added to theresidue. The solid product was collected by filtration and combined withthe product from another run starting from 16.00 g. of17a-methy1estradiol methyl ether. The combined product was dissolved inether, and the ether solution was washed twice with 500 cc. of water andonce with 500 cc. of saturated sodium chloride solution, and dried overanhydrous so-dium sulfate. Upon concentration of the ether solution,there was obtained 30.34 g. of 17ot-methyl- 2,5()-estradiene-3,17fi-diol3-methyl ether, M.P. 132- 141 C. when recrystallized from ether.

By replacement in the preceding preparation of the17e-methyl-3,17fi-estradiol 3-methyl ether by a molar equivalent amountof l7ot-propyl-3,17 S-estradiol E-methyl ether,17a-isopropyl-3,17,8-estradiol 3-methyl ether, or17e-butyl-3,17,8-estradiol 3-methyl ether (prepared by reacting estronemethyl ether with propylmagnesium halide, isopropylmagnesium halide, orbutylmagnesium halide, respectively), there can be obtained,respectively, 170:- propyl-2,5(10)-estradiene-3,17fl-diol 3-methyl ether[IV; R is (CH CH 17a-isopropyl-2,5(10)-estradiene-3, 17,8-diol 3-methylether [IV; R is CH(CH or 170cbutyl-2,5(10)-estradiene-3,17fl-diol3-methyl ether [IV; R is (CH CH (b) 1700metlzyl-19-n0r-5(10)-androsten-17B-0l-3-0ne [1; X is O, R is CH ].Asolution of 10.08 g. (0.08 mole) of oxalic acid dihydrated in 120 cc. ofwater was added to a solution of 6.04 g. (0.02 mole) of Not-methyl- 2,5(l0)-estradiene-3,17,B-diol 3-methyl ether in 600 cc. of methanol. Thereaction mixture was allowed to stand for forty minutes at roomtemperature and then was diluted with 4 liters of water. The solutionwas extracted twice with 1000 cc. of 2% sodium bicarbonate solution andthen washed with 500 cc. of saturated sodium chloride solution. Theaqueous layers were back extracted with 1 liter of ether which was inturn washed with 200 cc. of saturated sodium chloride solution. Thecombined organic extracts were dried over anhydrous sodium sulfate 7 andconcentrated by distillation. There was thus obtained 5.60 g. of17a-methyl-19-nor-5(10)-androsten-17,B-ol-3 one, M.P. 122134 C., whichwhen recrystallized successively from an ethyl acetate-hexane mixture,ethyl acetate and finally from ether was obtained in the form ofcolorless prisms, M.P. 140144.5 C. (corn);

(1% in chloroform;) ultraviolet maxima at 278 and 287 mu.

AnalysiS.CalCd. for C19H2802: C, H, Found: C, 79.40; H, 9.67.

.A mixed melting point of the 17OC-InBthy1-19-IlOT'5(10)-androsten-17fl-ol-3-one obtained above with 17u-methyl-19-nor-testosterone, M.P. 150.5157.5 C. (corn) showed a depression to129-138 C.

By replacement in the preceding preparation of the17a-rnethyl-2,5(10)-cstradiene-3,17fl-diol 3-methyl ether by a molarequivalent amount of 17oc-propyl-2,5(10)- estradiene-3,17fi-diol3-methyl ether, 17a-isopropyl-2, 5(10)-estradiene-3,17fi-diol 3 methylether, or 17a-butyl- 2,5 10)-estradiene-3,17B-diol B-methyl ether, therecan be obtained, respectively 17 a-propyl-19-nor-5 (10)-androsten-17/3-ol-3-one ['l; X is O, R is (CH CH 17a-isopropyl-19-nor-5(l0)-androsten-l7fi-ol-3-one [1; X is O, R is CH(CH or17a-butyl-19-nor-5(10)-androsten-17fl-ol- 3-one [1; X is O, R is (CH CHEXAMPLE 2 (a) 17et-erlzyl-3,17fi-estradi0l 3-methyl ether [111; R is C H].-A solution of 6.21 g. (0.02 mole) of 17aethynyl-3,17B-estradiol3-methyl ether, M.P. 152*1525 C., in 200 cc. of ethanol was hydrogenatedin the presence of 0.5 g. of 22% palladium hydroxide onstrontiumcarbonate catalyst at room temperature and an initial pressure of 58lbs. per sq. inch. After the calculated quantity of hydrogen had beentaken up, the reaction mixture was filtered, the filtrate concentratedand the residue recrystallized from methanol, givingl7a-ethyl-3,l7fi-estradiol B-methyl ether, M.P. 100l04 C.

:(b) 17c! ethyl-2,5 (10)-cstradiene-3,17B-diol 3-methyl ether [IV; R isC H was prepared from 10.00 g. of 17aethyl-3,17fl-estradiol B-methylether, 6.00 g. of lithium and 1000 cc. of liquid ammonia according tothe manipulative procedure described above in Example 1, part (a). Theproduct was recrystallized from other giving 6.18 g. of17a-ethyl-2,5(10)-estradiene-3,l7;3-diol 3-methy1 ether, M.P. 116.5-124C.

(c) 1 7u-ethyl-19-n0r-5(10)-audr0sten-17fl-0l-3-one [1; X is O, R is C11 was prepared from 6.18 g. of 17a.-ethyl-2,5(10)-estradiene-3,17/3-diol 3-methyl ether and 5.80 g. ofoxalic acid dihydrate according to the manipulative procedure describedabove in Example 1, part (b). The product was dissolved in pentanecontaining 10% ether and chromatographed on a column of 300 g. of silicagel. The column was eluted with pentane-ether mixtures of increasingother content. Pentane containing 40% ether brought out 2.72 g. of17a-ethyl-19-nor5(10)-androsten-17fl-ol-3-one, colorless prisms, M.P.134.5-1385 C. (corn) when recrystallized from ethyl acetate and dried invacuo at C. for thirteen hours;

(1% in chloroform); ultraviolet maximum at 282 m Analysis.-Calcd. forGZQHBOOZ: C, 79.42; H, 10,00. Found: C, 79.73; H, 9.83.

EXAMPLE 3 l7a-methyl-19n0r-5(l0)-andr0Stene-3,17fi-di0l [1; X is OH, Ris CH ].A suspension of 3.79 g. (0.100 mole) of lithium aluminum hydridein cc. of ether was stirred for one hour. There was then added over aperiod of one and one-half hours a solution of 4.17 g. (0.0145 mole) of17a-rnethyl-19-n0r-5(l0)-androstcn-17fi-ol-3- one in 175 cc. of ether.The reaction mixture was stirred for one hour, refluxed for four hoursand allowed to stand at room temperature overnight. Ethyl acetate (30cc.) was then added during one hour, and the mixture was stirred for twohours at room temperature and poured into 1 liter of ice watercontaining 50 cc. of concentrated hydrochloric acid. The product wasextracted with ethyl acetate, and the extracts were washed withsautrated sodium chloride solution and dried over anhydrous sodiumsulfate. The dried solution was concentrated and recrystallized fromethyl acetate and from methanol, giving 2.39 g. of17a-methyl-19-nor-5(10)-androstene-3,17;3-diol in the form of colorlessprisms, M.P. 168172 C. (corn); [a] =+l31.0 (1% in chloroform).

Analysis.Calcd. for C H O C, 78.57; H, 10.41. Found: C, 78.53; H, 10.20.

By replacement in the preceding preparation of the 170:-methyl-19-nor-5(10)-androsten-17p-ol-3-one by a molar equivalent amountof 17a-ethy1-l9-nor-5(10)-androsten- 17fi-ol-3-one, 17a-propyl-19-nor-5(10) -androsten-17/3-ol- 3-one, l7e-isopropyl-19-nor 5(10)androsten-17fl-ol-3- one, or17a-butyl-19-nor-5U0)-androsten-l7fiol-3-one, there can be obtained,respectively, 17u-ethy1-l9-nor- 5(l0)-androstene-3,17fi-diol [I; X isOH, R is C H 17apropyi-19-nor-5(l0)-andostene-3,l7/3-dio1 [1; X is OH, Ris (CH CH 17u-isopropyl-19-nor-5 l0 -androstene- 3,17fi-diol [1; X isOH, R is CH(CH or l7a-butyll9-nor-5(10)-androstene-3,l7fi-diol {1; X isOH, R is (CH CH The compounds of our invention possess useful estrogenicactivity. For example, 17m-rnethyl-19-nor-5(lO)- androstene-3,17fl-diol,was found to be stimulating as an estrogen at dose levels of *O .25-6.25mg. per kg. per day. 15 52,905,676

The compounds of the invention can be prepared for use by dispersingthem in an aqueous suspension by means of detergents and thickeningagents, or by dissolving them in a therapeutically acceptable oil oroil-Water emulsion for parenteral administration.

We claim:

1. A 17u-(iower-a1kyl)-l9-nor-5(10)-androstene-3,17fldiol.

References Cited in the file of this patent UNITED STATES PATENTS ColtonJuly 15, 1958 Colton Sept. 22, 1959

1. 17A-(LOWER-ALLKYL)-19-NOR-5 (10)-ANDROSTENE-3,17BDIOL.